GLIAA: FET-PET- vs. MRI-based re-irradiation in recurrent glioblastoma. A prospective randomized trial.

Introduction: The objective of this study was to assess the potential improvement in outcome for patients with recurrent glioblastoma (rGBM) undergoing re-irradiation by employing a radiotherapy target volume delineation based on O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET), in comparison to the delineation based on contrast-enhanced T1-weighted magnetic resonance imaging (T1Gd-MRI).

Methods: We report on a prospective, multicenter, randomized clinical trial (NOA 10/ARO 2013-1, DKTK-a., GLIAA). Patients with a detectable rGBM of 1-6 cm were randomized 1:1 at 14 centers in Germany between a FET-PET-based target volume delineation (experimental arm A) and a T1Gd-MRI-based target volume delineation (control arm B) and received high-precision stereotactic re-irradiation with 39 Gy à 3 Gy, 5x/week. Randomization was centralized, computerized and stratified using a minimization algorithm. Response was evaluated by MRI, and suspected progression was confirmed by FET-PET or histology, where possible. Primary endpoint was progression-free survival (PFS) from randomization. Secondary endpoints were overall survival (OS), locally controlled survival (LCS), recurrence patterns, differences between target volumes, quality of life, safety and toxicity. The trial was approved by the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM - Germany) and is registered with ClinicalTrials.gov (NCT01252459), the German Clinical Trials Register (DRKS00000634) and the European Clinical Trials Database (EudraCT-No. 2012-001121-27).

Results: Between November 26, 2013, and September 2, 2021, 271 patients were assessed for eligibility and 200 were randomized between FET-PET-based (n=100) and GdT1-MRI-based (n=100) target volume delineation. N=98 patients in the FET-PET arm and n=97 patients in the T1Gd-MRI arm were treated per protocol. Median PFS was 4.0 months (95% confidence interval [CI] 3.7-5.2) in the FET-PET arm and 4.9 months (95% CI 3.7-6.0) in the GdT1-MRT arm (one-sided stratified log-rank test p=0.98; adjusted HR for the experimental versus the control arm 1.14 [95% CI 0.85-1.52], p=0.39;). Median OS was 9.4 months (95% CI 7.8-11.1) in the FET-PET arm and 9.0 months (95% CI 7.6-10.5) in the GdT1-MRI arm (HR 1.01 [95% CI 0.75-1.37], p=0.92). Median LCS was 6.3 months (95% CI 5.1-7.2) in the FET-PET arm and 6.8 months (95% CI 6.2-7.3) in the GdT1-MRI arm (HR 1.20 [95% CI 0.88-1.62], p=0.25). Local control rate at 12 months was 22% in the FET-PET arm (95% CI 14%-31%) and 20% in the GdT1-MRI arm (95% CI 12%-29%). In 60 patients with progression in the experimental arm, 45.0% of recurrences were in field, 28.3% out of field, and 21.7% marginal. In 57 patients with progression in the control arm, 47.4% relapsed in field, 31.6% out of field, and 14.0% marginal. Radiation necrosis was documented in 25.5% of cases in the FET-PET arm and in 21.6% in the GdT1-MRI arm. Out of 239 patients who received the FET tracer, 9 reported 13 adverse events and 3 reported 5 SAEs in the timespan of 7 days after FET-PET. No event was related to the application of the FET tracer.

Conclusions: This trial did not reveal a discernible advantage of FET-PET-based re-irradiation when compared to GdT1-MRI-based treatment for patients with rGBM. Consequently, clinicians are free to opt for either modality for target volume delineation in this context. The FET-PET investigation proved well-tolerated in all instances. Given the inclusion of only FET-PET-positive patients, the findings of this trial do not influence the diagnostic utility of FET-PET in distinguishing tumor progression from post-therapeutic changes.